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【medical-news】PTC124或许抑制与囊性纤维化有关的
Laurie Barclay, MD
August 22, 2008 — The new, orally administered drug PTC124 (PTC Therapeutics) may signal a paradigm shift for treatment for nonsense-mutation cystic fibrosis (CF), according to the results of a phase 2 prospective trial reported Online First in the August 21 issue of The Lancet. By suppressing nonsense mutations, PTC124 reduces the epithelial electrophysiological abnormalities caused by the transmembrane conductance regulator (CFTR) dysfunction in patients with CF.
"This study demonstrates the potential for personalized medicine, combining selection of patients with a specific type of genetic mutation and a drug treatment that has been specifically designed to overcome that mutation," lead author Eitan Kerem, MD, head of pediatrics and the [CF] center at the Hadassah University Hospital in Mount Scopus, Jerusalem, said in a news release. "The publication of these ground-breaking results in the Lancet offers new hope to those patients with CF due to a nonsense mutation in the CFTR gene and establishes a path forward for evaluating the efficacy and long-term safety of PTC124."
CF results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for CFTR in about 10% of patients worldwide. PTC124 is a small molecule designed to produce functional CFTR by inducing ribosomes to selectively read through premature stop codons during mRNA translation.
In this study, 23 adults with CF, with a median age of 25 years and who had 1 or more nonsense mutations in the CFTR gene, were recruited and evaluated in 2 cycles, each lasting 28 days. More than 90% of patients had severe CF, with impaired pulmonary function, respiratory infection with Pseudomonas or other pathogens, and pancreatic insufficiency.
Patients received PTC124, 16 mg/kg per day in 3 doses every day for 14 days, during the first cycle, followed by 14 days without treatment. In the second cycle, patients received 40 mg/kg of PTC124 in 3 doses every day for 14 days, followed by 14 days without treatment.
The main endpoints were change in CFTR-mediated total chloride transport, proportion of patients who responded to treatment, and normalization of chloride transport, as measured by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course and after 14 days without treatment.
Transepithelial nasal PD was assessed in 23 patients in the first cycle and in 21 patients in the second cycle. In the first treatment phase, mean total chloride transport increased (change of −7.1 ?7.0 mV; P < .0001). In the second treatment phase, change was −3.7 ?7.3 mV (P = .032).
Response in total chloride transport, defined as a change in nasal PD of at least −5 mV, occurred in 16 of 23 patients in the first cycle's treatment phase (P < .0001) and in 8 of 21 patients in the second cycle (P < .0001). Normalization of total chloride transport occurred in 13 of 23 patients in the first cycle's treatment phase (P = .0003) and in 9 of 21 in the second cycle (P = .02).
"In patients with [CF] who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction," the study authors write.
Pulmonary function testing and body weight also improved in patients receiving PTC124. The drug was well tolerated overall, with more than 90% treatment compliance in all patients. No drug-related serious adverse events were reported, although 2 patients receiving PTC124 had constipation without intestinal obstruction and 4 had mild dysuria.
"We are very pleased by this positive outcome from our ongoing collaboration with PTC," said Preston Campbell, III, MD, executive vice president of medical affairs at the Cystic Fibrosis Foundation. "The development of PTC124 fits well with our strategic goal of supporting approaches that have the potential to modify the course of CF. We are continuing to work together with PTC [Therapeutics] and the broader CF medical community to support the next steps in the evaluation of PTC124 for the clinical benefit for the treatment of nonsense-mutation CF."
On the basis of these findings, the manufacturer plans to begin a phase 2b trial later this year to assess the clinical benefit of PTC124 in adults and children with nonsense-mutation-mediated CF.
"The publication of these data provides clinical proof of concept in CF for the PTC124 mechanism of action in overcoming nonsense mutations as the basis for treating genetic disease," said Stuart W. Peltz, PhD, president and chief executive officer of PTC Therapeutics. "Given the potential applicability of PTC124 to multiple genetic disorders, we have a pivotal study of PTC124 for nonsense-mutation Duchenne/Becker muscular dystrophy ongoing and are planning proof-of-concept studies in additional genetic disorders."
PTC Therapeutics and Cystic Fibrosis Foundation Therapeutics supported this study. Eight of the study authors have received funding support from PTC Therapeutics for this study and have also received compensation for time, effort, and travel expenses. Four other authors are employees of PTC Therapeutics.
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作者:admin@医学,生命科学 2010-10-06 05:11
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